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The sorbitol pathway: effect of streptozotocin induced diabetes and the feeding of a sucrose-rich diet on glucose, sorbitol and fructose in the retina, blood and liver of rats.

The sorbitol, fructose and glucose content of the retina, blood and liver from normal and streptozotocin diabetic rats fed either a starch- or sucrose-rich diet for 15 days has been determined. The sorbitol and fructose level in the retina was much higher than that in either the liver or blood and was significantly increased in diabetes on either diet. Such increases in the sorbitol concentration did not occur in either the liver or the blood during diabetes, and the possibility that the sorbitol pathway can play an important metabolic role in the diabetic retina has been discussed. The feeding of a sucrose- as opposed to a starch-rich diet did not significantly alter the concentrations of glucose, sorbitol or fructose in the normal rat retina but caused a marked elevation in the diabetic state.

Animals

[Influence in vivo of sorbitol on sorbitol dehydrogenase activity].

Previous researches carried out on the metabolism of sorbitol in the rat showed the influence of this polyalcohol on the activity of some dehydrogenases NAD and NADP-dependent and on lacate/pyruvate, NADH/NAD and NADPH/NADP ratios. Since sorbitol dehydrogenase (SDH, EC 1.1.1.14) is an enzyme with a great affinity for sorbitol, it seemed interesting to investigate the effect of a sorbitol-enriched diet on SDH activity in the rat liver after different periods of dietary treatment (20, 40, 60 days). SDH was assayed by a continuous optical test according to Bücher et al. The data obtained show a repressive action on SDH activity by a sorbitol-enriched diet. In fact, whilst after 20 days of treatment SDH activity decreased of about 18% in respect of the controls, after 60 days a decrease of 80% was observed. This result is so interesting to stimulate other investigations in vitro on the kinetics of such metabolic reaction in the attempt to explain the relation between the enzyme and its substrate.

Animals

[Parenteral administration of sorbitol solution and its impact on sorbitol, glucose, fructose and lactate concentration in the blood of cattle, sheep and piglets].

Significant rise of fructose in the blood plasma of cattle resulted from an application of sorbite solution (0.5 g sorbite per kg live weight), with its onset as early as during the infusion. The highest concentration was reached 15 minutes after completion of infusion. Rise in glucose (11 mg/100 ml plasma on average) failed to prove statistically significant and dropped temporarily (after 60 to 120 minutes) below the original value. The lactate level in the blood went up temporarily and reached its maximum 30 minutes from the end of infusion. Sorbite solution (1 g/kg live weight) was intravenously applied to sheep and tock fructose to its maximum after 30 minutes. Intraperitoneal application of sorbite solution (1 g/kg live weight) was tolerated well also by piglets and triggered an age-dependent decline of glucose in blood plasma.

Animals

Conversion of glucose to sorbitol and fructose by liver-derived cells in culture.

Conversion of glucose to fructose and sorbitol is documented in rat hepatoma-derived cultured cells (HTC cells). After addition of 5.5 mM [U-14C]glucose to incubation medium, labeled sorbitol and fructose accumulated intracellularly at a linear rate over a period of 60 min. The sugars were isolated, identified, and quantitated by paper chromatography, gas-liquid chromatography, and enzymatic phosphorylation of fructose. Primary culture of adult rat hepatocytes was analyzed similarly and demonstrated no significant accumulation of labeled fructose or sorbitol. The basis for this difference between HTC cells and primary hepatocyte culture was examined both in terms of enzyme activities that mediate the formation of sorbitol and fructose and in terms of the catabolism of these sugars. Both types of culture (as well as extracts of intact rat liver) exhibited enzymatic activities catalyzing the conversion of glucose to sorbitol (aldose reductase) and sorbitol to fructose (sorbitol dehydrogenase). However, the cultures differed strikingly with regard to the catabolism of sorbitol and fructose. The conversion of labeled sorbitol to metabolites in HTC cells was negligible; by contrast, hepatocytes in primary culture utilized the sugars at rates comparable to that of glucose, which may account for the lack of their accumulation in primary culture. The findings suggest that the conversion of glucose to sorbitol and fructose by HTC cells may represent a retained normal liver function, one which is amplified by the inability of HTC cells to dispose of these sugars.

Aldehyde Reductase

The localisation of sorbitol pathway activity in the rat renal cortex and its relationship to the pathogenesis of the renal complications of diabetes mellitus.

A series of in vivo and in vitro investigations was performed to examine the localisation of sorbitol pathway activity in the rat renal cortex and to investigate the possible relation that the acculumation of sorbitol pathway intermediates in renal cortical tissue may have to the pathogenesis of renal complications in diabetes mellitus. Neither of the sorbitol pathway intermediates, sorbitol or fructose, were detected either in intact glomeruli which had been isolated from rats rendered chronically diabetic with streptozotocin, or in metabolically active glomeruli which had been incubated in vitro in high glucose media. Such data agreed with previously published observations that the enzyme aldose reductase is not present in renal glomeruli, and suggested that changes in sorbitol pathway activity cannot be directly related to the pathogenesis of diabetic glomerulosclerosis. Sorbitol was detected in low concentrations (3.1 mu-mol/g protein) in cortical tubules which had been isolated from the renal cortex of rats rendered chronically diabetic with streptozotocin. This concentration of sorbitol was higher than that in the intact renal cortex of the diabetic animal (0.3 mu-mol/g protein) or in the cortical tubules of non-diabetic animals (0.5 mu-mol/g protein). It is apparent that the renal cortical tubule is a major site of sorbitol pathway activity in the renal cortex. However, there is presently no obvious causal relationship between the accumulation of such relatively low concentrations of sorbitol in the renal cortical tubule and the pathogenesis of glomerulosclerosis or cortical tubular lesions in diabetes.

Animals

Antiketogenic action of fructose, glyceraldehyde, and sorbitol in the rat in vivo.

The purpose of this study was to compare the metabolism and antiketogenic properties of fructose, glyceraldehyde, and sorbitol. Fructose, glyceraldehyde, and sorbitol were readily metabolized and exhibited an antiketogenic effect in both blood and liver when injected intramuscularly to starved (forty-eight hours) rats. Sorbitol had the most pronounced antiketogenic effect and produced an 80 to 90 per cent decrease in the blood ketone bodies sixty minutes after administration. Fructose and glyceraldehyde were equally effective and produced about a 60 to 70 per cent decrease in ketone bodies. Fructose, glyceraldehyde, and sorbitol caused a significant decrease in the concentration of hepatic ketone bodies. In liver, sorbitol was found to be most effective in its antiketogenic action. The concentration of plasma free fatty acids remained unchanged after injection of all three antiketogenic substrates. Fructose, glyceraldehyde, or sorbitol caused increased blood lactate and pyruvate concentrations, and fructose was the most effective of the three substrates. Fructose administration resulted in a significant decrease in hepatic lactate/pyruvate and beta-OH-butyrate/acetoacetate concentration ratios, whereas sorbitol caused an increase in the concentration ratio of these two substrat pairs. Decreases in blood and liver ketone body levels were associated with lowering of liver acetyl-CoA concentration . However, the decrease in hepatic acetyl-CoA produced upon the administration of antiketogenic substrates was not pronounced. Sorbitol administration resulted in the most pronounced increase in hepatic alpha-glycerophosphate concentration. Fructose or glyceraldehyde also caused an increase in alpha-glycerophosphate content. Administration of each of the three antiketogenic substrates produced an increase in hepatic dihydroxyacetone phosphate concentration. All three antiketogenic compounds increased liver glycogen and blood glucose concentrations. No significant changes were observed in hepatic ATP, ADP, or AMP concentrations sixty minutes after the injections of any of the antiketogenic substrates. Although decreased liver acetyl-CoA levels were associated with the antiketogenic effects of the compounds tested, the increased liver alpha-glycerophosphate content best explains the differences between fructose or glyceraldehyde and sorbitol.

Acetyl Coenzyme A

Relationship of endogenous to dietary sorbitol. A study in normal and diabetic rats.

The relationship of endogenous to dietary sorbitol was investigated by measuring the sorbitol content of plasma, lens and kidney in normal an streptozotocin-injected rats fed for two-three weeks a control diet or a diet rich in either sorbitol or sucrose. The insulin content and secretory capacity of the pancreatic islets removed from these rats was also measured. In normal rats, the carbohydrate-rich diet increased the concentration of sorbitol in plasma but not lens or kidney. The carbohydrate-rich diet also increased the secretory responsiveness of the B-cell to glucose. Accumulation of sorbitol in lens and kidney occurred in diabetic rats. When the diabetic rats were treated with insulin, the sorbitol content of plasma and lens was less elevated than in untreated diabetic animals, despite poor control of the glycemia. The insulin treatment failed to prevent sorbitol accumulation in the kidney. There was no obvious difference between dietary sorbitol and sucrose respectively, in terms of sorbitol accumulation in tissues or stimulation of B-cell secretory potential.

Animals

Remineralizing potential, antiplaque and antigingivitis effects of xylitol and sorbitol sweetened chewing gum.

The objective of this study was to investigate the effects of xylitol and sorbitol sweetened chewing gums on plaque accumulation, gingival inflammation and remineralizing potential of plaque following six weeks of use. Twenty-eight consenting individuals were randomly assigned to each of three phases (six weeks in duration) consisting of chewing xylitol gum, chewing sorbitol gum and a non-chewing phase. Subjects chewed one stick after every meal and at two other times for a total of five sticks per day. At the completion of each treatment phase, plaque and gingival indexes were performed and plaque was later collected. Calcium concentration in plaque was determined by atomic absorption spectophotometry. Reductions in plaque indexes were significant for both xylitol gum (p < 0.001) and sorbitol gum (p < 0.05) when compared to the no chewing period. The gingival indexes reflected a decrement in gingival inflammation with both xylitol and sorbitol, though only sorbitol values were statistically significant (p < 0.05). Chewing xylitol and sorbitol gums reduced plaque accumulation and gingival inflammation. In addition, both gums enhanced the remineralization potential of plaque. Xylitol gum showed a superior effect with respect to remineralization potential and plaque reduction. Sorbitol gum had a superior effect on gingival health but not significantly so.

Calcium

Quantitative histochemistry of the sorbitol pathway in glomeruli and small arteries of human diabetic kidney.

Recent evidence has suggested a role for the polyol pathway in pathogenesis of cell damage in diabetes Glucose may be phosphorylated to glucose-6-phosphate via hexokinase and enter glycolysis or reduced to sorbitol via aldose reductase to enter the polyol pathway. The poorly diffusible sorbitol is converted via sorbitol dehydrogenase to fructose. Hexokinase, aldose reductase and sorbitol dehydrogenase activities were measured in glomeruli (G) and small arteries (SA) taken from normal and diabetic human kidneys, Hexokinase in diabetic G was 1688, which was significantly decreased from normal, 3147 mmoles/kg-1/h-1. Alodse reductase was significantly elevated in diabetic G,56-6, compared to normal G,10-8 mmoles/kg-1/h-1. In contrast, sorbitol dehydrogenase was significantly depressed in diabetic G, 3-7 VERSUs 10-9 mmoles/kg-1/h-1. The enzymatic changes observed in diabetic G would facilitate accumulation of sorbitol and therefore could contribute to the progression of glomerulosclerosis. The activity of hexokinase was also significantly reduced in SA, whereas aldose reductase and sorbitol dehydrogenase were unchanged.

Diabetes Mellitus

The comparative bioavailability of Lanoxin tablets and Lanoxicaps with and without sorbitol.

(1) The mean cumulative urinary digoxin excretion over 8 days was compared in 8 healthy volunteers after single doses of digoxin administered as 3 Lanoxin tablets of 0.25 mg, 3 digoxin tablets of 0.2 mg, 12 Lanoxicaps without sorbitol of 0.05 mg, 6 Lanoxicaps without sorbitol of 0.1 mg digoxin, 3 Lanoxicaps without sorbitol of 0.2 mg and 3 Lanoxicaps with sorbitol of 0.2 mg. (2) There was no significant difference between the 8 day cumulative urinary excretion for any of the Lanoxicaps treatments. (3) Cumulative urinary excretion after 3 digoxin tablets of 0.2 mg was significantly (P less than 0.05) lower than after all other treatments. (4) Cumulative urinary excretion after 3 Lanoxin tablets of 0.25 mg was not significantly different from that after any of the Lanoxicaps treatments except 0.1 mg Lanoxicaps without sorbitol, it was significantly (P less than 0.05) lower after the latter. (5) Mean urinary excretion of digoxin was 60% of ingested dose for all Lanoxicaps treatments and was significantly (P less than 0.05) higher than the mean value of 50% for both tablet treatments. (6) Enhanced absorption of digoxin from Lanoxicaps was confirmed and shown to be unrelated to the sorbitol content of the capsule shell.

Adult

[Severe side-effects during peritoneal dialysis caused by sorbitol-containing dialysate (author's transl)].

In seven patients with chronic renal failure in an advanced stage 17 episodes of upper abdominal pain, hypertension, vomiting and (in some of them) coma occurred during peritoneal dialysis with sorbitol-containing dialysate. The signs recurred in some of the patients but did not when glucose-containing dialysate of otherwise identical composition was used. Very high levels of sorbitol in CSF and serum were measured in the comatose patients. The precipitating factor is probably a reduced metabolic breakdown of sorbitol in renal failure with preferential intracellular deposition of sorbitol and subsequent cellular oedema. To avoid this dangerous reaction it is necessary to use glucose instead of sorbitol in peritoneal dialysates, despite the technical problems of sterilisation. Where this is not possible, glucose should be added in order to reduce the sorbitol concentration in the dialysate to less than 15g/l.

Adult

A comparison between two hypotonic irrigating solutions used in transurethral resections of the prostate: sorbitol (2%)-mannitol (1%) and 1.5% glycine solutions.

Two hypotonic but non-haemolysing irrigating solutions, sorbitol-mannitol (2% + 1%) and glycine (1.5%), were compared in 40 TURP cases using a continuous resection technique. Ethanol (1%) was added to the irrigating fluid as a marker to make possible early detection of fluid absorption by breath analysis. Mannitol and sorbitol were determined in plasma and urine; glycine and ethanol were determined in plasma. Apparent absorbed fluid volumes were calculated from the immediate postoperative plasma concentrations of ethanol, mannitol, sorbitol and glycine and from the elimination of mannitol in urine during 24 hours following the operation. The use of a continuous operating technique with a suprapubic trocar resulted in very small absorptions (less than 1 l) in this series. The concentrations of the two solutes in the sorbitol-mannitol irrigating fluid were balanced so that the plasma concentrations immediately postoperatively were of the same order when absorption occurred. The sorbitol concentration declined more rapidly than the mannitol concentration in conformity with previous findings. In most cases the peak plasma level was observed immediately postoperatively but in some cases at a later time (during the interval 0-2 hours), indicating absorption from a depot of fluid accumulated extravesically in addition to direct intravenous absorption. The best estimate of fluid absorption seems to be obtained from the urinary elimination of mannitol, followed by estimates based on the plasma mannitol concentration immediately postoperatively. The plasma ethanol level determined at the same time gave an estimate of the same order, whereas plasma sorbitol and glycine levels gave lower estimates (owing to rapid redistribution and metabolism).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged

Uptake of sorbitol by chick embryo heart cells at various stages of development.

Sorbitol enters chick embryo heart cells from five days of development on. The rate of sorbitol entry becomes slower as development proceeds and the data suggest this is principally due to an increase in the apparent Km of transport, the Vmax remaining relatively constant. The uptake of sorbitol displays saturation kinetics and is believed on this ground to be carrier-mediated. Sorbitol does not appear to be actively transported since it is not concentrated against a gradient and its uptake is not inhibited by iodoacetate or 2, 4-dinitrophenol. Sorbitol does not appear to be taken up via the glucose transport system since uptake is not stimulated by insulin or inhibited by glucose or phloretin.

Animals

Sorbitol in isolation of rat pancreatic islets. Effects on islet yield, insulin secretion and accumulation of inositol phosphates.

Tissue aggregation and exocrine contamination are problems encountered in gradient separation of pancreatic islets. Here we report that sorbitol used as an osmotic component in Percoll gradients gives a low ionic strength gradient with improved purity of islet fraction, less islet aggregation and reduced time for final manual rinsing following separation in gradients with NaCl as osmotic component. Previous reports have indicated that long-term (weeks) exposure to high sorbitol concentrations leads to low intracellular levels of inositol phosphates and subsequent effects on the intracellular signal transduction in cells. In our model, short-term exposure to high sorbitol concentrations had no effect on the accumulation of the inositol phosphates or insulin secretion caused by glucose. On the other hand, sorbitol increased the basal insulin secretion three-fold, apparently via a non-stimulatory mechanism. Therefore, we conclude that sorbitol is preferable to NaCl as the osmotic component in Percoll gradient separation of rat pancreatic islets, although long-term exposure should be avoided due to potential toxic effects.

Animals

The comparative oxidation of glucose, fructose, sorbitol and xylitol in normal man.

The aim of the study was to compare the effects of fructose, sorbitol and xylitol with those of glucose on blood glucose and insulin levels and carbohydrate utilization in man. The experiment was performed by means of continuous indirect calorimetry in five groups of five to six normal volunteers during infusion of either glucose, fructose, sorbitol, xylitol or a mixture of fructose, glucose and xylitol in the proportion of 2:1:1. Glucose and insulin did not present any important variations during the fructose, sorbitol and xylitol infusiosns. However, carbohydrate oxidation rose significantly during administration of these substrates. Carbohydrate oxidation rose 80 mg/min for fructose, 27 mg/min for sorbitol, 39 mg/min for xylitol and 75 mg/min for the carbohydrate mixture, in comparison to 101 mg/min for glucose. It is concluded that fructose, sorbitol and xylitol provoke an increase in carbohydrate utilization without a corresponding rise in glycemia and insulinemia.

Adult

Acid production from Lycasin, maltitol, sorbitol and xylitol by oral streptococci and lactobacilli.

The acid production from maltitol was compared with the acid production from hydrogenated starch hydrolysate (Lycasin), sorbitol and xylitol by a number of oral strains and reference strains of Streptococcus mutans, S. sanguis, S. salivarius, S. mitior, S. milleri, S. faecalis, S. faecium, S. avium, Lactobacillus casei and L. salivarius. The polyols were added to a final concentration of 1.0% to two different basal media. Incubation was performed at 37 degrees C for 7 days after which the pH was recorded. Maltitol was fermented only by the lactobacilli (about two thirds of the strains). Lycasin was fermented by all strains of S. faecalis, more than 90% of the lactobacilli, about half of the S. sanguis strains, about one third of the S. mutans strains, and by a few other streptococcal strains. Acid production from sorbitol was observed among more than 80% of the S. mutans strains and the S. faecalis strains and most of the lactobacilli strains. Sorbitol-fermenting strains of S. sanguis and of S. mitior, all isolated from sorbitol-consumers, were observed. No other sorbitol-fermenting streptococci were found. Only the reference strains L. salivarius subsp. salivarius ATCC 11741 and S. avium ATCC 14025 fermented xylitol.

Acids

Effects of 3 months frequent consumption of hydrogenated starch hydrolysate (Lycasin), maltitol, sorbitol and xylitol on human dental plaque.

Lozenges containing hydrogenated starch hydrolysate (Lycasin), maltitol, sorbitol or xylitol were consumed 4 times daily during 3 months by 4 groups of persons (in all 85 subjects). In the maltitol-, sorbitol- and xylitol-group the plque wet weights were of the same magnitude before and after the test period. In the Lycasin-group, a higher value was found after than before the 3-month period (p less than 0.01). The acid production in suspensions of dental plaque material from Lycasin, maltitol and sorbitol expressed as per cent of that from glucose was approximately the same before and after the test period. From xylitol no acid production could be demonstrated either before or after the 3-month period. There were no statistically significant differences between the plaque pH-changes induced by rinsing with 50% solutions of Lycasin, maltitol, sorbitol or xylitol before and after the test period. However, there was a tendency (p less than 0.05) towards lower pH-values induced by the maltitrol and sorbitol rinse after the 3-month period compared with before. No difference in the relative numbers of facultative anaerobic streptococci. Streptococcus mutans or facultative anaerobic lactobacilli before and after the test period was found.

Adult